Seizures occur when the excitability of brain circuits exceeds the restraints imposed by inhibitory mechanisms. Glutamate is the predominant excitatory transmitter in the central nervous system. Thus an increased number of glutamate synapses, enhanced glutamate synaptic function, and increased extracellular glutamate concentration would be expected to facilitate seizures. An increase in the number of recurrent excitatory synapses has been documented in many persons with epilepsy and replicated in animal models. Moreover, potentially epileptogenic changes in glutamate mechanisms and the properties of glutamate synapses have been found. Reported differences between epileptic and non-epileptic human brain tissue include increased extracellular glutamate concentration, reduced glutamine synthetase expression and activity, increased phosphate-activated glutaminase activity, reduced plasma membrane glutamate transport, up regulation of AMPA receptor expression/function in neurons and astrocytes, and enhanced expression/function of NR1-NR2B NMDA receptors. Data from animal models support the view that these differences contribute to circuit hyperexcitability. Glutamate mechanisms may therefore provide novel targets for the prevention and treatment of epilepsy. However, the epileptogenic potential of altered glutamate mechanisms depends on where in the brain the change is expressed and the utility of drugs that attack these mechanisms depends on the ability to target them specifically to regions of hyperexcitability.
Epilepsy may be defined as a disorder of brain function characterized by the repeated and unpredictable occurrence of seizures. Seizures involve the disordered, rhythmic, and synchronous firing of CNS neuron populations. Seizures originate in neuronal populations capable of bursting, develop because of an imbalance between neuronal excitation and inhibition, and are characterized by high-frequency firing associated with membrane depolarization. Neuronal excitation and inhibition may become unbalanced in many different ways. This article focuses on the contribution to seizures of glutamate synaptic plasticity, both anatomical plasticity that creates new excitatory synapses and functional plasticity that enhances the efficacy either of excitatory synapses or of glutamate itself. Observations made with human tissue are emphasized.
Glutamate is the principal excitatory neurotransmitter in mammals. About 60–70% of all synapses in the CNS appear to be glutamate synapses. Glutamate also serves as the principal neurotransmitter utilized by sensory neurons. Autonomic neurons and motoneurons are about the only excitatory neurons in mammals that utilize a transmitter other than glutamate. Thus the formation of enhanced or novel glutamate circuits, enhanced excitatory transmission, and/or an excess of glutamate itself could disrupt the balance of excitation and inhibition leading to the occurrence of seizures.
STRENGTHENING OF RECURRENT EXCITATION
Many cases of epilepsy arise from lesions of the brain. The consequences of brain injury depend not only on the degeneration of neurons and their axonal projections but also on reactive growth triggered by the injury. Degeneration of axonal projections stimulates the growth of collateral fibers from uninjured axons followed by a process termed “reactive synaptogenesis.”1 In many instances, axon sprouting and synaptogenesis appear to serve as mechanisms of repair. That is, the degenerated axons are replaced by new projections of the same type. The end result may be the restoration of at least some normal function. In contrast, the focal lesions often associated with epileptogenesis initiate the strengthening of recurrent excitatory circuitry. In humans with epilepsy, this phenomenon is most clearly observed in the dentate gyrus. Reorganization of the dentate gyrus is of particular interest because this region normally imposes a high resistance to the propagation of seizures from the highly-excitable entorhinal cortex to the equally excitable CA3 area of the hippocampus. The principal neurons of the dentate gyrus, the granule cells, are normally difficult to activate, both individually and as a population. The difficulty of activating synchronous population discharge can be explained, in part, by the scarcity of recurrent excitatory connections among dentate granule cells. The relative independence of granule cell activity is required to support the function of these cells in mediating pattern separation during the formation of new memories. Most persons with temporal lobe epilepsy exhibit a type of CNS pathology known as hippocampal sclerosis. Within the hippocampus, the most consistent region of neuronal loss is the hilus of the dentate gyrus. Loss of the hilar mossy cells opens synaptic territory on the proximal part of the granule cell apical dendrite. For reasons that remain unclear, denervation of this dendritic region attracts neoinnervation primarily from the axons of other granule cells. Granule cell axons, the mossy fibers, sprout new collaterals and form recurrent excitatory connections. Because mossy fiber terminals contain numerous densely-packed synaptic vesicles that contain zinc, mossy fiber sprouting can be detected by the Timm stain, which visualizes vesicle-bound zinc. Several investigators used this approach to demonstrate mossy fiber sprouting in hippocampal tissue resected for medically-intractable temporal lobe epilepsy.2–5 In addition, the new mossy fiber terminals were visualized with an antibody to dynorphin, a neuropeptide contained in those terminals.6 Formation of recurrent excitatory circuitry in the human dentate gyrus is associated with a reduced threshold for granule cell synchronization.7,8 The formation or strengthening of recurrent excitatory circuitry is one mechanism that could synchronize neuronal firing and thus support the initiation or propagation of seizures.
Robust mossy fiber sprouting has been observed in all animal models of epilepsy characterized by the loss of hilar mossy cells.9,10 Studies of these models have generally confirmed the role of recurrent mossy fibers in synchronizing granule cell firing and supporting population bursts. Dentate granule cells are unusual in that they continue to be born and differentiate throughout life. Strong seizures increase the rate of granule cell neurogenesis markedly, and postseizure-generated granule cells possess properties distinct from those of pre-existing granule cells. Many retain the hilar basal dendrite and burst potential characteristic of immature granule cells and they serve as prominent sources and recipients of recurrent mossy fiber innervation. Granule cell basal dendrites provide a target for recurrent mossy fiber synapses in addition to the proximal apical dendrite. In humans, unlike rodents, about 25% of dentate granule cells normally have a basal dendrite. Thus recurrent excitation of granule cells may be a normal feature of human brain, which is then enhanced by mossy fiber sprouting during epileptogenesis. About 95% of recurrent mossy fiber synapses are made with other granule cells and only 5% with inhibitory neurons. Frequency facilitation at mossy fiber-granule cell synapses operates over a rather narrow dynamic range (0.8–2 Hz), but even small changes in excitatory transmission could substantially increase synchronized granule cell discharge, especially if some granule cells generate a burst of action potentials. Thus the normally rather quiescent dentate gyrus may be driven into reverberating epileptiform activity under conditions that strongly engage the novel recurrent dentate gyrus circuitry.
Recurrent axon sprouting is not confined to the dentate gyrus. In animal models of epilepsy, the number of monosynaptic recurrent excitatory synapses also increases dramatically in area CA1 of the hippocampus and the neocortex. Some seizures appear to propagate directly from the entorhinal cortex to area CA1, bypassing the dentate gyrus.11 In these instances, the enhancement of recurrent excitation in area CA1 would appear of greater importance than changes in the dentate gyrus. Further studies are needed to determine how widespread the strengthening of recurrent excitation is in different regions of the brain, how large a role this type of plasticity plays compared to other changes that take place in the epileptic brain, and, importantly, the extent to which this type of plasticity outside the dentate gyrus occurs in the brain of humans with epilepsy.
EXTRACELLULAR GLUTAMATE CONCENTRATION
Measurements of extracellular glutamate concentration by microdialysis have revealed, as expected, an increase immediately before and during seizures in humans with epilepsy.12,13 Perhaps less expected is the finding that the extracellular glutamate concentration is also elevated during the interictal period. This occurs despite neuronal loss and glial proliferation. Normally, the extracellular glutamate concentration is maintained in the low micromolar range. In one study, the extracellular glutamate concentration of the hippocampus was found to be 4 to 5-fold greater in patients with temporal lobe epilepsy than in controls.14 This difference was only observed in brain regions from which seizures are thought to originate. A high ambient extracellular glutamate concentration could, among other actions, evoke a tonic NMDA current in neurons nearby, chronically depolarize those neurons, enhance neuronal excitability by activating Type I metabotropic receptors, and in extreme situations initiate an apoptotic/necrotic cascade. Mechanisms potentially responsible for increasing extracellular glutamate concentration include enhanced biosynthesis, enhanced release, impaired metabolic inactivation, and impaired clearance from the extracellular space.
Glutamate can be synthesized by at least six different metabolic routes. However, perhaps 80% of the glutamate used as a transmitter by CNS neurons is synthesized from glutamine by phosphate-activated glutaminase. The mitochondria of glutamate terminals express this enzyme in abundance. Glutamine produced within astrocytes diffuses into the extracellular space and is taken up by nerve terminals. It is then hydrolyzed to glutamate by phosphate-activated glutaminase. Cytoplasmic glutamate is then made available for release through transport into synaptic vesicles by a specific vesicular transporter.
One study of human hippocampi resected for medically-intractable temporal lobe epilepsy indicated enhanced expression and activity of phosphate-activated glutaminase per neuron in some regions.15 Hippocampal enzyme activity was greater in the damaged hippocampus of lesional temporal lobe epilepsy than in the intact hippocampus of other forms of temporal lobe epilepsy. Thus enhanced production of glutamate may contribute toward increasing its ambient extracellular concentration.
Glutamate produced by intraterminal mitochondria is taken up into a population of synaptic vesicles that is specialized for this purpose. The expression of vesicular glutamate transport determines that a particular synaptic terminal will release glutamate.16 Four vesicular transporters have been identified. Two of these, designated VGLUT1 and VGLUT2, are expressed by synaptic vesicles of glutamate pathways. VGLUT1 is the type most frequently expressed in forebrain regions. A third vesicular transporter, VGLUT3, is expressed by synaptic vesicles of some non-glutamate pathways, including pathways that release serotonin or dopamine. Synaptic terminals of these pathways contain largely or completely separate populations of glutamate and non-glutamate vesicles. Expression of VGLUT3 in some synaptic vesicles endows these pathways with the ability to release some glutamate along with their predominant transmitter. The physiological role of glutamate co-release is unclear. Finally, sialin, a lysosomal H+/sialic acid cotransporter, accumulates glutamate and aspartate in synaptic vesicles by a mechanism independent of sialic acid transport.17 Sialin is the only vesicular transporter identified thus far that can transport aspartate; the other excitatory amino acid vesicular transporters are highly specific for glutamate. Transport is driven by an inside-positive vesicular membrane potential that is created by an electrogenic proton pump. Glutamate is then released upon nerve terminal depolarization by Ca2+-dependent exocytosis. In most instances, when the action potential invades the synaptic terminal, Ca2+ entry releases the contents of either one or zero glutamate vesicles and the quantity of glutamate released is normally sufficient to saturate the postsynaptic receptors. However, both multiquantal release and lack of receptor saturation have been reported at some glutamate synapses. Glutamate regulates its further release by feeding back onto terminal autoreceptors. Glutamate release is also regulated by the previous activity of that terminal, other transmitters present locally in the extracellular fluid, and products of cell metabolism, most notably adenosine and arachidonic acid.
No studies of synaptic glutamate release from epileptic human tissue have been reported. However, three studies that utilized either an electrophysiological approach18 or depolarization by elevated K+19,20 in animal models of temporal lobe epilepsy indicated an enhancement of glutamate release. Both approaches evoked predominantly the exocytotic release of glutamate from nerve terminals. Astrocytes can also release glutamate, by both exocytotic and non-exocytotic mechanisms. Indirect evidence suggests that epileptogenesis may increase the capacity of astrocytes to release glutamate.21 Enhanced expression of the flip splice variants of AMPA receptors by astrocytes has been reported in lesional temporal lobe epilepsy.22 Activation of these receptors by extracellular glutamate, in conjunction with the activation of Type I metabotropic receptors, would be expected to evoke intracellular Ca2+ oscillations that could potentially drive astrocytic glutamate release. However, enhanced astrocytic release has not been demonstrated in either human tissue or animal models. Although enhanced neuronal release clearly could account, at least partly, for the increased ambient extracellular glutamate concentration in epileptic brain, it is not clear to what extent glial release of glutamate contributes to the extracellular pool.
Conversion to Glutamine
As described above, glutamine is the primary substrate for the biosynthesis of the glutamate transmitter pool. The biosynthesis of glutamine involves a cooperativity between glutamate nerve terminals and the adjacent astrocytes. Glutamate released from nerve terminals is transported into astrocytes and converted to glutamine by glutamine synthetase, an enzyme expressed by astrocytes but not by neurons. The glutamine synthetase reaction requires ATP. Astrocytic end-feet, enriched in glucose transporters, cover virtually all capillary walls in the brain. Glutamate transport into astrocytes stimulates glucose uptake by these cells. Glutamine produced by the astrocyte diffuses into the extracellular space, where it is available for uptake by glutamate terminals and subsequent conversion to glutamate. This cooperative metabolic pathway involving two distinct cell types is referred to as the glutamate-glutamine cycle. The glutamate-glutamine cycle provides a mechanism for coupling glutamate transmission with glucose utilization, one of the signals detected by PET imaging. The energy demands of this cycle account for ~85% of total brain glucose utilization.23
Glial proliferation (gliosis) is a prominent feature of damaged brain regions in lesional epilepsies. Reactive astrocytes have a reduced expression of glutamine synthetase. Thus the immunoreactivity and total enzymatic activity of glutamine synthetase are reduced markedly in regions of neuronal loss, despite glial proliferation.24–26 Similar results have been reported in animal models.27–31 Congenital loss of glutamine synthetase results in seizures and death within days after birth.32 Moreover, reducing the expression or activity of glutamine synthetase in animals either causes seizures or increases seizure susceptibility.26,33–34 Thus the conversion of glutamate to glutamine may be viewed as a neuroprotective measure intended, in part, to prevent the hyperactivation of glutamate receptors by extracellular glutamate. Failure of this mechanism in lesional epilepsies may contribute to the increase in extracellular glutamate concentration, leading in turn to seizure generation and excitotoxic cell death.
Plasma Membrane Transport
High-affinity (1–10 μM KT) excitatory amino acid transporters expressed on the cell surface bind glutamate after its synaptic release, thus clearing the synaptic cleft in preparation for the next presynaptic action potential and limiting the spillover of glutamate from the cleft. The latter effect inhibits glutamate from activating extrasynaptic receptors or receptors located at nearby synapses. Because NMDA receptors bind glutamate with high affinity, distant NMDA receptors would be activated inappropriately if much glutamate were to escape the synaptic cleft routinely. In addition, transporters limit activation of the postsynaptic Group I and presynaptic Group II metabotropic glutamate receptors that lie in proximity to, but outside, the synaptic cleft. Maintenance of a low extracellular glutamate concentration is also necessary to prevent excitotoxicity. Indeed knockout or knockdown of excitatory amino acid transporters in animals results in seizures and neurodegeneration.35–37 In addition to limiting the extracellular concentration of glutamate, presynaptic excitatory amino acid transporters recover transmitter for reuse and astrocyte transporters accumulate glutamate for use as the metabolic precursor for glutamine. Transport activity requires energy, and both the direction and rate of transport depend on the extracellular Na+ and intracellular K+ concentrations.
Cloning studies identified five excitatory amino acid transporters, two mainly glial and three neuronal. EAAT1 (GLAST) and EAAT2 (GLT-1) are expressed mainly by astrocytes, with EAAT2 predominating. In fact, EAAT2 accounts for 1% of total astrocyte protein and for ~90% of glutamate removal from the extracellular space. EAAT2 is also expressed to some degree by most glutamate neurons and has been localized to the plasma membrane of the synaptic terminal. Synaptic terminal expression of EAAT2 presumably explains the robust glutamate transport found in synaptosome preparations. EAAT3 (EAAC1) is expressed on the postsynaptic surface at glutamate synapses. EAAT4 is expressed largely by cerebellar neurons and EAAT5 by photoreceptors and bipolar cells of the retina.
In lesional epilepsies, one might expect increased expression of glial excitatory amino acid transporters because of the increase in glial membrane surface. In contrast, most reports have indicated reduced EAAT2 immunoreactivity and protein in regions of neuronal loss.38–42 Similar to glutamine synthetase, expression of EAAT2 may be down regulated in reactive astrocytes. Alternative splicing of EAAT2 mRNA in patients with temporal lobe epilepsy may lead to reduced protein levels.43 Because glutamate is cleared from the extracellular space predominantly by the action of EAAT2, down regulation of this transporter might well account for the high ambient extracellular glutamate concentration observed in the same brain regions. In addition, a chronic deficiency in glutamate transport might raise the extracellular glutamate concentration sufficiently to promote additional neuronal injury and death. However, two studies found no change in the expression of EAAT2.44–45 The reason for this discrepancy is unclear. Aside from possible differences in technique, it is also possible that the different laboratories studied patients having different seizure etiologies, with a different treatment history, and/or having suffered brain damage at different times before the tissue was excised. None of the human studies included measurement of transport activity, only transporter protein. Therefore the functional status of EAAT2 in human epilepsy remains uncertain. Studies of animal models are similarly conflicted; both reduced20,46–47 and unchanged48–49 expression of EAAT2 have been reported.
In contrast to EAAT2 expression, studies of both excised human tissue38–40,44 and animal models20,48,50–51 revealed the enhanced expression of EAAT3 by surviving neurons in damaged regions of epileptic brain. Up regulation of EAAT3 at postsynaptic sites may represent an attempt by surviving neurons to protect themselves from the deleterious effects of an increased extracellular glutamate concentration. However, the functional significance of this change has not been investigated.
Glutamate acts upon several structurally and pharmacologically different types of membrane receptor. The “ionotropic receptors” are themselves cation channels composed of multiple subunits, whereas the “metabotropic receptors” operate through G-protein coupling. For historical reasons, the ionotropic glutamate receptors are named for structural analogues of glutamate that activate receptors of that particular class selectively.
The vast majority of glutamate synapses operate through postsynaptic AMPA and NMDA receptors. Kainate receptors are expressed prominently on the presynaptic membrane, postsynaptic membrane, or both at some glutamate synapses. AMPA receptors are expressed by astrocytes as well as neurons. Cloning studies justified the original separation of ionotropic glutamate receptors into classes based on agonist pharmacology. Glycopolypeptide subunits that participate in receptor assembly within one class exhibit much greater sequence homology than subunits that contribute to receptors of the other two classes.
The metabotropic glutamate receptors have been subdivided into three groups based on their agonist affinities and their preferred signal transduction pathways. Group I metabotropic glutamate receptors signal mainly through the activation of phospholipase C (mGluR1, mGluR5). Group I receptors are located postsynaptically, but outside the synaptic cleft. They are also expressed by astrocytes. Neuronal postsynaptic Group I receptors are activated mainly during high frequency activity when glutamate overflows the synapse. Group I receptors on astrocytes respond to changes in the ambient extracellular glutamate concentration. Receptor activation enhances excitability and causes release of Ca2+ from intracellular stores. One type of Group II metabotropic glutamate receptor, mGluR2, is located typically on the preterminal portion of the axon. This receptor is activated only when glutamate overflows the synapse. Activation of these receptors reduces subsequent glutamate release. The other type of Group II metabotropic glutamate receptor, mGluR3, appears to be expressed predominantly by glial cells. Group III metabotropic glutamate receptors are particularly sensitive to the glutamate analogue L-AP4. There are four receptors in this class, designated mGluR4, mGluR6, mGluR7, and mGluR8. mGluR6 serves as the postsynaptic receptor for glutamate at the synapse in the retina between the photoreceptor cell and the bipolar cell. mGluR4, mGluR7, and mGluR8 are expressed in a largely non-overlapping pattern on terminals of glutamate pathways in the brain. They are located at the release sites; receptor activation reduces subsequent glutamate release. It appears that Group III receptors regulate glutamate release regardless of presynaptic action potential frequency, whereas mGluR2 functions in this way only when a high presynaptic firing frequency results in overflow of glutamate from the synaptic cleft. Firing frequencies as low as 3 Hz have been associated with glutamate overflow onto mGluR2 receptors.
Nearly all glutamate-activated fast EPSPs depend on the activation of AMPA receptors. For AMPA receptors in particular and ionotropic glutamate receptors in general, the receptor is composed of four glycopolypeptide chains (subunits) arranged like the staves of a barrel with a channel in the middle through which cations can flow. AMPA receptors bind glutamate with low affinity (KD ~100 μM) and in most instances desensitize rapidly. All AMPA channels are permeable to both Na+ and K+. Because the inward Na+ flux exceeds the outward K+ flux (ENa,K ≈ 0 mV), the net effect is a depolarization: the fast EPSP. The underlying synaptic current is the fast EPSC.
Four subunits, designated GluR1-GluR4 (or GluA1-GluA4 or GluRA-GluRD), contribute to AMPA receptors. Each of these subunits can exist in “flip” and “flop” versions dependent on alternative splicing. The involvement of the flip versus flop version of the subunit in channel formation affects the extent of receptor desensitization, with flip subunits promoting less desensitization and thus more prolonged channel opening. Flip subunits are more commonly expressed during ontogenic development than in the adult brain. AMPA receptor subunits can form a channel either by themselves (homomeric channels) or with other subunits (heteromeric channels). The great majority of AMPA receptors expressed by excitatory neurons and many AMPA receptors expressed by inhibitory neurons include one or two GluR2 subunits. In this instance, the channel lacks permeability to Ca2+. However, AMPA receptors expressed by astrocytes and many other inhibitory neurons lack a GluR2 subunit. Therefore the channel is permeable to Ca2+, in addition to Na+ and K+. Finally, the subunit composition of postsynaptic AMPA receptors is influenced by previous synaptic activity at that site. For example, in the basal state postsynaptic AMPA receptors expressed by excitatory neurons are composed mainly of GluR2 and GluR3 subunits. Calcium/calmodulin-dependent (CaM) kinase II becomes activated during high-frequency activity as a result of NMDA channel opening (see below). CaM kinase II phosphorylates cytoplasmic GluR1 subunits, causing GluR1-GluR2 receptors to be inserted into the postsynaptic membrane. There is thus a net increase in the number of synaptic AMPA receptors, and the new receptors differ in subunit composition from the pre-existing receptors. This is part of the molecular basis for the important biological process known as NMDA receptor-dependent long-term potentiation (LTP). LTP is thought to be the elemental process that underlies declarative memory and types of learning that depend on formation of these memories.
Studies of excised tissue from epileptic human brain have indicated up regulation of neuronal AMPA receptors in certain brain regions. AMPA receptor binding associated with the dendrites of dentate granule cells was increased in persons with lesional temporal lobe epilepsy,52 as was GluR1 immunoreactivity of CA3 hippocampal cells and hilar mossy cells.53 These results are consistent with hyperexcitability driven by enhanced AMPA receptor activation. In some animal models, expression of GluR2 mRNA and protein are reportedly down regulated.40,54–55 This change would be expected to increase the proportion of Ca2+-permeable AMPA receptors and thus total Ca2+ influx in postsynaptic neurons. It has also been reported in animals that seizure-induced neuronal degeneration is preceded by down regulated expression of GluR2.56 Thus loss of GluR2 may lead to excitotoxic cell death.
Reactive astrocytes in sclerotic hippocampi of persons with temporal lobe epilepsy exhibit enhanced expression of flip splice variants, which may cause prolonged astrocyte depolarization and Ca2+ influx.22 No such change was found in the undamaged hippocampi of persons with non-lesional temporal lobe epilepsy. Increased cytoplasmic Ca2+ in astrocytes could lead to astrocytic Ca2+ waves that trigger glutamate release from those cells. Thus AMPA receptor plasticity in astrocytes may contribute to the increased extracellular glutamate concentration in lesional forms of temporal lobe epilepsy.
NMDA receptors normally coexist with AMPA receptors in the postsynaptic membrane. The extent to which NMDA receptor activation contributes to the EPSP depends on the resting membrane potential of the postsynaptic cell. Its contribution increases as the membrane potential becomes less negative. At most synapses, the NMDA receptor plays a negligible role in the EPSP evoked by a single impulse because the channel is blocked by Mg2+ ions. The binding of Mg2+ to the open channel is voltage-dependent; Mg2+ binds much less strongly when the membrane is depolarized. Thus NMDA receptors are activated significantly only when glutamate release is paired with postsynaptic depolarization. In response to a single impulse, glutamate released from the synaptic terminal produces a depolarization by activating AMPA receptors. However, this EPSP is too short-lived to relieve much of the Mg2+ block. The EPSP is short-lived because (1) the AMPA receptor desensitizes rapidly when activated by glutamate, (2) the AMPA receptor has a low affinity for glutamate, causing bound glutamate to dissociate from the receptor rapidly, and (3) the following IPSP returns the membrane potential toward the resting value. During repetitive activity, however, the postsynaptic depolarization is more prolonged and the Mg2+ block is effectively relieved. In addition, repetitive activity reduces GABA inhibition. Under these conditions, the NMDA receptor contributes substantially to the EPSP. In comparison to the AMPA receptor-mediated component, the NMDA component is of longer duration and exhibits slow kinetics. In general, the NMDA receptor serves as a mechanism by which experience alters synaptic transmission and properties of the postsynaptic cell for a period of hours-to-years. High-frequency activity is associated with experiences that result in memory and learning. High-frequency activity can also be pathological, as in seizures.
Both the long-lasting changes in synaptic function and NMDA receptor-induced pathology depend on the permeability of NMDA channels to Ca2+. Like the AMPA receptor, it is the large fluxes of Na+ and K+ through the open channel that account for the NMDA component of the EPSC and EPSP. In contrast, the smaller Ca2+ influx is responsible for altering the properties of the synapse and the postsynaptic cell. Because the intracellular Ca2+ concentration at rest is very low, even a small influx of Ca2+ can increase the local intracellular concentration substantially. At this higher concentration, Ca2+ activates a number of key enzymes and transcription factors whose concerted action leads to a long-lasting enhancement of the EPSP and, in the extreme, to cell death.
Forebrain NMDA receptors are composed primarily of three subunits designated NR1, NR2A, and NR2B. Each receptor consists of two NR1 subunits and two NR2 subunits. Glutamate binds to the NR2 subunit, whereas the NR1 subunit binds the essential co-activator glycine. NR1-NR2B receptors exhibit much slower decay kinetics than NR1-NR2A receptors. Thus the charge transferred per channel opening is much greater. Glutamate synapses in developing forebrain utilize predominantly NR1-NR2B receptors. During the maturation of the forebrain, NR1-NR2A receptors are inserted into the postsynaptic membrane and NR1-NR2B receptors are relegated largely to extrasynaptic sites. However, both NR1-NR2A and NR1-NR2B receptors can be found in both locations.
With respect to NMDA receptors, the most interesting finding reported in studies of resected human tissue is the often increased expression of NR2B mRNA and the increased function of NR1-NR2B receptors in damaged regions of epileptic brain,57–59 even though total NMDA receptor expression may be down regulated.52 Because responses mediated by NR1-NR2B receptors decay more slowly than those mediated by NR1-NR2A receptors, the associated Ca2+ influx would be enhanced. A large influx of Ca2+ through NMDA channels may facilitate seizure generation and influx through extrasynaptic NR1-NR2B receptors can precipitate excitoxicity.60 Of particular interest is the finding of increased NR2A and NR2B mRNA expression in dentate granule cells of persons with lesional temporal lobe epilepsy.57 Studies of animal models suggest enhanced NMDA receptor function at perforant path synapses on these cells.18,61 In addition, NMDA receptors are expressed on some populations of glutamate synaptic terminals. In this location, tonic activation of these receptors by extracellular glutamate facilitates glutamate release. In an animal model of temporal lobe epilepsy, presynaptic NMDA receptors of the entorhinal cortex were found to be up regulated.62 Because the entorhinal cortex is thought to be essential for the propagation of limbic seizures and of neocortical seizures into the limbic system, NMDA receptor-induced potentiation of glutamate release in that region may be significant.
The kainate receptor resembles the AMPA receptor with respect to structure, regulation, and ionic selectivity. Kainate activates both AMPA and kainate receptors; there is considerable overlap in agonist action on the two receptors. Kainate receptors tend to be most abundant in those brain regions where NMDA receptors are least abundant. Their kinetic properties are intermediate between those of AMPA and NMDA receptors. Thus simultaneous activation of postsynaptic AMPA and kainate receptors prolongs the response to glutamate and may result in repetitive firing of the postsynaptic cell. Kainate receptors are present on some glutamate preterminal axons and on portions of the synaptic terminal outside the synaptic cleft. Some glutamate terminals, including the mossy fiber terminals of the hippocampus, express both high- and low-affinity kainate receptors. They are activated when glutamate overflows the synaptic cleft during repetitive activation of the presynaptic neuron. Activation of low-affinity presynaptic kainate receptors depolarizes the terminal, reducing subsequent glutamate release by limiting action potential-evoked Ca2+ influx. Activation of high-affinity presynaptic kainate receptors prolongs the action potential-induced depolarization and enhances Ca2+ entry into the terminal. Thus Ca2+ influx may be enhanced or reduced by kainate receptor activation, depending on the magnitude and duration of presynaptic depolarization and on the local extracellular glutamate concentration. By enhancing Ca2+ influx, kainate receptor activation mediates the dramatic frequency facilitation observed at mossy fiber synapses on CA3 hippocampal pyramidal cells. Kainate receptors are also expressed by inhibitory neurons, where their activation can both stimulate and depress GABA release.
Three subunits that bind agonist with low affinity (GluR5-7) and two subunits that bind agonist with high affinity (KA1-2) contribute to kainate receptors. Native receptors are composed of either a combination of low- and high-affinity subunits or exclusively of low-affinity subunits. Kainate receptors normally form a channel permeable just to Na+ and K+. However, some kainate receptors that contain GluR5 or GluR6 subunits are also permeable to Ca2+ (due to lack of RNA editing).
Compared to AMPA and NMDA receptors, the status of kainate receptors in epileptic brain has been little studied. Expression of GluR5 and GluR6 mRNA was reportedly decreased per CA2/CA3 pyramidal cell in the hippocampus of persons with temporal lobe epilepsy, whether or not the hippocampus was damaged.63 In contrast, KA2 and GluR5 mRNAs were up regulated in dentate granule cells of patients with sclerotic hippocampi. The latter finding suggests the production of additional presynaptic kainate receptors needed to regulate transmission at newly-formed recurrent mossy fiber synapses. In the temporal neocortex and hippocampus of humans with epilepsy, the editing efficiency of GluR5 and GluR6 subunits is reportedly enhanced.64,65 This may be regarded as a compensatory response to seizures, reducing Ca2+ influx through kainate channels. Studies of animal models have not yielded consistent changes in kainate receptor expression, and possible changes in kainate receptor function have not been assessed.
Metabotropic Glutamate Receptors
Because metabotropic glutamate receptors are quite heterogeneous with respect to signal transduction and localization, their activation may alter seizure generation and propagation in diverse ways. Stimulation of Group I metabotropic receptors in the hippocampus transforms normal neuronal activity into prolonged epileptiform discharge. This may come about through the metabotropic receptor-related activation of a voltage-gated cation current expressed in CA3 pyramidal cells.66 In addition, the liberation of Ca2+ from intracellular stores that is driven by activation of Group I metabotropic receptors in astrocytes, combined with Ca2+ influx through AMPA channels, triggers Ca2+ waves and subsequent astroglial glutamate release. Strong co-activation of AMPA and Group I metabotropic glutamate receptors in neurons can raise intracellular Ca2+ concentration by enough to provoke long-lasting potentiation of the EPSP. Activation of Group II or Group III metabotropic glutamate receptors reduces transmitter release. The effect on seizures depends on whether the receptor is expressed by excitatory or inhibitory presynaptic elements and on the role of those particular synapses in circuit excitability. However, the overall effect of activating these receptors is likely to be inhibitory toward seizure generation and propagation.
Little is known about the role of metabotropic glutamate receptors in human epilepsy, although excessive activation of Group I receptors may account for seizures in persons with Fragile X syndrome.67 Studies of animal models, however, suggest down regulation of Group II and Group III metabotropic receptors.68–72 In pilocarpine-treated mice, for example, feedback regulation of glutamate release from medial perforant path terminals in the dentate gyrus was found to be compromised.69 Regulation of lateral perforant path transmission by feedback activation of mGluR8 was unchanged. In pilocarpine-treated rats, however, autoregulation through mGluR8 was reduced.68 In reactive astrocytes of the hippocampus, the immunostaining of mGluR3 and mGluR5 was reportedly increased in an electrical stimulation model of temporal lobe epilepsy.73 The combination of enhanced AMPA (see above) and Group I metabotropic receptor expression by astrocytes would be expected to increase cytoplasmic Ca2+ concentration in the presence of glutamate. Although much work on human tissue remains to be done, studies of animal models suggest that both enhanced activation of Group I metabotropic glutamate receptors and reduced autoregulation of glutamate release by Group II and Group III metabotropic receptors could facilitate spontaneous recurrent seizures.
SUMMARY AND FUTURE DIRECTIONS
Studies of glutamate pathways and synaptic mechanisms in human epilepsy have been limited by the restricted availability of tissue. This is especially true of biochemical and electrophysiological functions whose evaluation require fresh tissue. Nevertheless, studies to date suggest that epileptogenesis involves substantial plasticity of both glutamate circuitry and glutamate synaptic mechanisms, at least in regions of neuronal loss. These changes are predominantly in a direction that would be expected to promote hyperexcitability. An increased density of recurrent excitatory pathways may promote the synchronous discharge of principal neuron populations. A high ambient extracellular glutamate concentration may depolarize nearby neurons, evoke a tonic Ca2+ current by activation of extrasynaptic NMDA receptors, enhance neuronal excitability by activating Type I metabotropic glutamate receptors, and possibly initiate excitotoxicity. Several changes in glutamate mechanisms may act in concert to raise extracellular glutamate: enhanced biosynthesis from glutamine in nerve terminals, reduced conversion to glutamine by astrocytes, and down regulation of the glial plasma membrane transporter EAAT2. Studies of animal models suggest that enhanced glutamate release from both nerve terminals and astrocytes may also contribute. Glutamate receptor plasticity may also enhance neuronal excitability. Some evidence suggests enhanced AMPA receptor activation in both neurons and astrocytes, as well as enhanced expression and function of NR1-NR2B NMDA receptors. Although little is known about the status of glutamate metabotropic receptors in humans with epilepsy, studies of animal models suggest down regulation of inhibitory metabotropic receptors. Thus coincident sprouting of recurrent excitatory connections and altered pre- and postsynaptic glutamate mechanisms could potentially promote circuit hyperexcitability.
Given the exuberant sprouting of glutamate axons and apparently up regulated glutamate synaptic function in lesional epilepsy, there would appear to be great potential for the development of drugs that interfere with glutamate transmission to prevent seizures and drugs that interfere with glutamate plasticity to prevent the development of epilepsy after neuronal loss. However, the epileptogenic potential of these changes depends on where the change is expressed – excitatory vs inhibitory circuits, excitatory vs inhibitory neurons, and neurons vs glia. Although studies of animal models generally favor promotion of hyperexcitability, there has been no confirmation of this from human studies, apart from a few that focused on recurrent excitatory circuitry in the dentate gyrus. A major drawback to the development of glutamate-based drugs is that glutamate serves as the predominant excitatory transmitter throughout the CNS. Thus it is difficult to target therapy toward hyperexcitable brain tissue without causing adverse effects, even disturbing vital functions. Although mechanisms that regulate glutamate transmission differ in different excitatory pathways, nearly every form of regulation is repeated at many sites in the brain. The best way around this dilemma would be the development of agents that target glutamate circuits or mechanisms when they are overexpressed or overactive, but not when they are functioning normally. Conditional negative receptor modulators would be one example of such agents. The utility of memantine, a blocker of overactivated NMDA channels, as a treatment for Alzheimer’s disease serves as a precedent for the type of agent that might be clinically useful.
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J Victor Nadler.*
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National Center for Biotechnology Information (US), Bethesda (MD)
Nadler JV. Plasticity of Glutamate Synaptic Mechanisms. In: Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012.